Neurodegenerative diseases that affect Chamorros in the Mariana Islands of the Western Pacific resemble Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic Lateral Sclerosis (ALS) elsewhere, but ALS, PD and dementia frequently co-occur in Chamorros, and this syndrome is known as Guam ALS/Parkinson dementia complex (ALS/PDC). However, unlike AD, PD and ALS in other populations, Guam ALS/PDC is characterized predominantly by abundant neurofibrillary tangles (NFTs) in central nervous system (CNS) neurons that progressively degenerate. ALS/PDC NFTs are indistinguishable from those in classic AD, but about 25% of ALS/PDC brains contain AD-like senile plaque (SP) deposits of Ab, and PD-like Lewy bodies (LBs) were detected recently with antibodies to a-synuclein (a-syn) in more ALS/PDC brains than previously recognized indicating that ALS/PDC is not a "pure" tauopathy. However, the NFTs in both ALS/PDC and classic AD are intraneuronal aggregates of paired helical filaments (PHFs) formed by hyperphosphorylated tau (PHF-tau) composed of all 6 brain tau isoforms, while tau isoforms containing 3 or 4 microtubule binding repeats predominate in the tangles found in other tauopathies. Recently, we generated transgenic mice overexpressing 3R tau and surprisingly they developed an ALS/PDC-Iike phenotype to provide the first experimental evidence that NFT-like tau inclusions play a mechanistic role in ALS/PDC. Nonetheless, we also hypothesize that SPs and LBs contribute to the progression of ALS/PDC, and that oxidative/nitrative damage plays a role in the development of NFT which in turn contributes to mechanisms of SP and LB formation in this disorder. Thus, the Specific Aims of this project will test the hypothesis that brain degeneration in ALS/PDC results from accumulations of NFTs, SPs and LBs formed by tau, Ab and a-syn, respectively, that are induced to fibrillize and/or aggregate and oxidative/nitrative stress plays an important role in this process in ALS/PDC.